P620: DYNAMICS OF GENOMIC ABERRATIONS IN RELATION TO DISEASE ACTIVITY IN UNTREATED PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: V. Navrkalova, J. Kotaskova, K. Plevova, T. Reigl, M. Valisova, M. Bohunova, M. Zenatova, L. Radova, A. Panovska, S. Pospisilova
Journal: HemaSphere (2022)

Background: Chronic lymphocytic leukemia (CLL) manifests remarkable clinical variability linked with extensive heterogeneity of genomic defects. Despite the progress with novel therapeutic agents, some patients still face relapse and disease persistence due to subclonal populations, which harbor various somatic defects, growth dynamics, and therapy sensitivity. Clonal evolution of genomic defects was observed mainly in treated CLL patients, whereas progression and therapy need occur at some point during the disease course suggesting clonal dynamics even in untreated patients. Aims: To describe impact of clonal dynamics in gene mutations and chromosomal defects on clinical course of the disease in paired samples of untreated CLL patients. Methods: 200 samples from 100 CLL patients were analyzed by well-established comprehensive NGS panel LYNX (PMID 34082072) in two time points; at the diagnosis and before first therapy. Variants in 70 genes associated with B-cell malignancies, copy-number alterations (CNAs) and copy-neutral loss of heterozygosity (CN-LOH) across the whole genome were evaluated by a dedicated in-house bioinformatic pipeline. Clinical data were correlated with obtained results. Results: The surveillance period median between two sampling points was 36 months (range 7-174). One third of patients was still untreated during the follow-up (median 86 months, range 21-271), and the time to first treatment among 68 patients was 38 months (range 11-141). At the baseline, the most frequent defects were mutations in NOTCH1 (15 %), SF3B1 (15 %), ATM (12 %) genes, and 13q- (56 %), 11q- (19 %) and tri12 (15 %). We observed common clonal and subclonal co-occurrence of genomic defects in the pretreatment period. In sequential samples, we detected a change in the composition of genomic aberrations. Most alterations were stable (59 % mutations, 70 % chromosomal defects), but we observed dynamic changes in the rest with the predominance of growing allelic frequency and occurrence of new defects. Unsupervised clustering according to the presence of individual genomic defects with the emphasis on their dynamic changes and CLL driver attribute enabled to distinguish three clusters. The correlation with clinical data showed significant differences among clusters in IGHV status, CLL activity (categorized according to therapy need), and an increase of absolute lymphocyte count (ALC) per month. Obviously, the most adverse was cluster 1 with unmutated IGHV, rapid increase in ALC, and dynamics in CLL activity. Cluster 2 seemed to be intermediate and cluster 3 indolent. Groups also significantly differed in the presence and evolution of 11q-, 13q-, ATM mutations, tri12, chr13 LOH, 3p-, 2p+, chr9 LOH. Importantly, stable defects of chr13 were the most abundant in cluster 3, stable tri12 and expansions of 13q- in cluster 2, dynamics defects including 11q-, ATM mutations, 3p-, 2p+ and LOH 9 in cluster 1. Summary/Conclusion: In untreated CLL patients, clonal stable genomic defects prevail. However, common subclonal alterations and dynamic changes were observed in a considerable proportion of patients. After unsupervised clustering, a group of patients showing the most adverse clinical disease course harbored ATM defects, 3p-, 2p+, and chr9 LOH, possibly standing behind fast progression and therapy need. Hence, detailed monitoring of clonal evolution can help understand the heterogeneity in the CLL activity in the pretreatment period. Supported by AZV NV19-03-00091, MZ-CR RVO 65269705, MUNI/A/1330/2021.